Portal de Periódicos da CAPES

Competition of calcified calmodulin N lobe and PIP 2 to an LQT mutation site in Kv7.1 channel

2017; National Academy of Sciences; Volume: 114; Issue: 5 Linguagem: Inglês

10.1073/pnas.1612622114

1091-6490

William S. Tobelaim, Meidan Dvir, Guy Lebel, Meng Cui, Tal Buki, Asher Peretz, Milit Marom, Yoni Haitin, Diomedes E. Logothetis, Joel A. Hirsch, Bernard Attali,

Cardiomyopathy and Myosin Studies

Significance Voltage-gated potassium 7.1 (Kv7.1) channel and KCNE1 protein coassembly forms the I KS K + current that repolarizes the cardiac action potential, and mutations in Kv7.1 and KCNE1 genes cause cardiac arrhythmias. The proximal Kv7.1 C terminus binds calmodulin and the phospholipid phosphatidylinositol-4,5-bisphosphate (PIP 2 ); however, it is unknown whether their binding sites overlap physically and functionally. Here, we reveal the competition of PIP 2 and the calcified form of the calmodulin N lobe to a previously unidentified site in helix B of the proximal Kv7.1 C terminus. Notably, this site bears a mutation causing a cardiac arrhythmia called the long-QT syndrome. Our results suggest that, after receptor-mediated PIP 2 depletion and increased cytosolic Ca 2+ , calcified calmodulin N lobe interacts with helix B in place of PIP 2 to limit excessive I KS current depression.